Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
  • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention is directed to methods of treating postherpetic neuralgia in a mammal, preferably a human, wherein the methods comprise administering, preferably periodically administering, to an affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of a spiro-oxindole compound.
• Postherpetic neuralgia is a complication of herpes zoster (commonly known as shingles) in which pain persists for more than 3 months after resolution of the rash (three months is the most commonly identified duration, although definitions of duration for postherpetic neuralgia vary from more than 1 month to less than 6 years).
• Postherpetic neuralgia affects between 10% to 15% of people who have herpes zoster and increases with age, affecting up to 70% of those infected who are more than 70 years old (Davies, P. S. and Galer, B. S., Drugs 2004, Vol. 64, No. 9, pp. 937-47; Dubinsky, R. M. et al., Neurology 2004, Vol.
• Tricyclic antidepressants were the first analgesic agents that showed efficacy in randomized controlled trials of postherpetic neuralgia, and, subsequently, anticonvulsant agents, strong opioids, and topical analgesics have also demonstrated efficacy.
• lidocaine a nonselective sodium channel blocker
• US United States
• FDA Food and Drug Administration
• a subcommittee of the American Academy of Neurology determined that there was solid Class I evidence of efficacy for the lidocaine patch in postherpetic neuralgia (Dubinsky et al. 2004).
• the lidocaine patch if perhaps less effective than other approved treatments such as gabapentin and pregabalin (Dworkin, R. H. et al., Neurology 2003, Vol. 60, No. 8, pp.
• the present invention is directed to methods of treating postherpetic neuralgia in a mammal, preferably a human, wherein the methods comprise administering, preferably periodically administering, to an affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of a spiro-oxindole compound.
• one aspect of the invention is a method of treating postherpetic neuralgia in a mammal, wherein the method comprises administering, preferably periodically administering, to an affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of a spiro-oxindole compound having the following formula:
• Another aspect of the invention is a method of locally treating postherpetic neuralgia in a mammal with minimal or negligible systemic exposure of a spiro-oxindole compound, wherein the method comprises increasing the concentration of the spiro-oxindole compound defined above to a therapeutically effective amount in the affected skin area of the mammal by administering, preferably periodically administering, to the affected skin area a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of the spiro-oxindole compound.
• Another aspect is a method of treating postherpetic neuralgia in a mammal, wherein the method comprises administering, preferably periodically administering, to an affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of the spiro-oxindole compound and a therapeutically effective amount of one or more other therapeutic agents.
• the present invention is directed to methods of treating postherpetic neuralgia in a mammal, preferably a human, wherein the methods comprise administering, preferably periodically administering, to an affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of a spiro-oxindole compound.
• These methods provide minimal to negligible systemic exposure of the spiro-oxindole compound while effectively reducing the severity of the postherpetic neuralgia or alleviating the postherpetic neuralgia due to the increased concentration of the spiro-oxindole compound in the affected dermatome after the administration of the pharmaceutical composition to the affected skin area.
• a spiro-oxindole compound or “the spiro-oxindole compound” refers to the compound having the following formula:
• a chemical name for this compound is 1′- ⁇ [5-(trifluoromethyl)furan-2-yl]methyl ⁇ spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one.
• Active ingredient refers to the substance in a pharmaceutical composition which is biologically active.
• the active ingredient in the pharmaceutical compositions utilized in the methods of the invention is the spiro-oxindole compound.
• “Adverse Event” refers to any untoward medical occurrence in a patient administered a pharmaceutical product, regardless of whether it has a causal relationship with the treatment.
• An adverse event can therefore be any unfavorable and unintended physical sign, symptom or laboratory parameter that develops or worsens in severity during the course of the study, or significant worsening of the disease under study or of any concurrent disease, whether or not considered related to the study drug.
• a new condition or the worsening of a pre-existing condition will be considered an adverse event.
• Stable chronic conditions that are present before study entry and do not worsen during the study will not be considered adverse events.
• Affected skin area refers to the area of the skin of an affected dermatome of the mammal, preferably a human, where the postherpetic neuralgia is present.
• Affected dermatome refers to a dermatome of the mammal, preferably a human, which has had a herpes zoster skin rash and where postherpetic neuralgia is present.
• a dermatome is an area of skin supplied by sensory neurons that arise from a spinal nerve ganglion.
• the term “affected dermatome” may include more than one dermatome, preferably a dermatome contiguous with the original affected dermatome.
• Viruses, such as the varicella zoster virus, that lie dormant in nerve ganglia often cause rash and/or co-existing pain and, after the rash as abated, postherpetic neuralgia in a pattern defined by a dermatome. Such symptoms may not appear across the entire dermatome.
• X refers to an interval extending from X minus 10% of X to X plus 10% of X and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
• % w/w refers to a percentage by weight compared to the total weight of the composition being considered.
• Baseline refers to that information which is gathered at the beginning of a study from which variations found in the study are measured. Baseline can also be described as a known value or quantity with which an unknown is compared when measured or assessed.
• Postherpetic neuralgia is a classical neuropathic pain condition in which damage to peripheral sensory nerves (and the dorsal horn regions of the spinal cord) by the varicella zoster virus is believed to generate spontaneous peripheral neural discharges that lead secondarily to hyperexcitability of dorsal horn sensory neurons and result in exaggerated central nervous system (CNS) responses to all input, a condition known as central sensitization (Kost and Straus 1996).
• CNS central nervous system
• patients with postherpetic neuralgia have both a zone of loss of sensation and zones of altered sensation to light touch and temperature in the dermatome which exhibited the herpes zoster rash.
• Pain is described as deep aching or burning in quality and may be triggered by non-painful stimulus (mechanical allodynia) or temperature change (warm or cold allodynia). It may last for years, although there is a tendency for it to wane over time. In those patients whose pain is persistent and severe, postherpetic neuralgia becomes debilitating, markedly restricting the patient's activity and quality of life.
• postherpetic neuralgia is defined as pain present for more than 3 months and less than 6 years after the onset of herpes zoster skin rash affecting a single dermatome (i.e., primary dermatome), pain present more than 6 months and less than 6 years after the onset of herpes zoster skin rash, pain present more than 6 months and less than 5 years after the onset of herpes zoster skin rash, pain present more than 6 months and less than 4 years after the onset of herpes zoster skin rash, pain present more than 6 months and less than 3 years after the onset of herpes zoster skin rash, pain present more than 6 months and less than 2 years after the onset of herpes zoster skin rash, pain present more than 6 months and less than 1 year after the onset of herpes zoster skin rash, or pain present more than 3 months and less than 1 year after the onset of herpes zoster skin rash, or pain present more than 3 months
• more than one dermatome may be included, provided the affected dermatome is contiguous with the primary dermatome. Allodynia (pain due to a stimulus that does not usually provoke pain) and/or hyperalgesia (increased pain from a stimulus that usually provokes pain) may be present with postherpetic neuralgia.
• Excipient includes, without limitation, any inactive material that is combined with a spiro-oxindole compound of the invention in order to produce a pharmaceutical composition of the invention for topical administration.
• the term “excipient” is intended to include, but is not limited to, any solvents, penetration enhancing agents, antioxidants, stiffening agents (i.e., thickeners), ointment bases, antioxidants, adsorbents, demulcents, emollients, preservatives, moisturizers, buffers, adjuvants, carriers, diluents, dye/colorants, solubilizers (including surfactants), wetting agents, dispersing agents, suspending agents, sunscreen agents and stabilizers.
• “Pharmaceutically acceptable excipient” refers to an excipient, as defined above, which has been approved by a regulatory agency, such as for example, but is not limited to, the United States Food and Drug Administration, the European Medicines Agency or Health Canada, as being acceptable for use in a formulation for the topical administration of a pharmacologically active ingredient, and/or are considered as Generally Recognized As Safe materials (GRAS materials), and/or are listed in the Inactive Ingredients Guide published by the United States Food and Drug Administration. “Pharmaceutically acceptable excipients” can also comprise the acceptable excipients listed in Remington: The Science and Practice of Pharmacy , Fox, 21 st ed. 2005. Exemplary excipients include, but are not limited to, the following:
• Periodically administering or “periodic administration” as used herein refers to the initial application of a topical pharmaceutical composition of the invention to the affected skin area of the mammal, preferably a human, and then subsequent applications at pre-determined periods of time after the initial application to reduce the severity of the postherpetic neuralgia and/or to alleviate the postherpetic neuralgia.
• Systemic effect refers to a medical treatment effect that affects the body as a whole, rather than just one part.
• Minimal or negligible systemic exposure refers to an insignificant concentration of the spiro-oxindole compound in the plasma and tissues of a mammal when compared to the concentration of the spiro-oxindole compound in the affected skin area after the administration of a pharmaceutical composition of the invention comprising the spiro-oxindole to the affected skin area.
• the affected skin area includes the affected dermatome and the muscle and nerve tissues within the affected dermatome.
• minimal or negligible systemic exposure occurs when the concentration of the spiro-oxindole compound in the plasma and tissues of the mammal, excluding the affected skin area, is from about 5-fold to about 100-fold less, preferably from about 5-fold to about 50-fold less, more preferably from about 10-fold to about 40-fold less, even more preferably from about 15-fold to about 25-fold less, and most preferably about 20-fold less than the concentration of the spiro-oxindole compound in the affected skin area after administering a pharmaceutical composition of the invention comprising the spiro-oxindole compound to the affected skin area.
• “Therapeutically effective amount” as used herein refers to that amount of a topical pharmaceutical composition of the invention or that amount of the spiro-oxindole compound in the topical pharmaceutical compositions of the invention, when administered, preferably periodically administered, to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of postherpetic neuralgia in the mammal and with minimal or negligible systemic exposure of the spiro-oxindole compound to the mammal.
• the amount of the topical pharmaceutical composition of the invention or the spiro-oxindole compound which constitutes a “therapeutically effective amount” will vary depending on the nature of the postherpetic neuralgia and its severity, other conditions (e.g., sex, age, weight, general health) affecting the health of the human to be treated, and the manner of administration, as well as upon the effectiveness of the pharmaceutical composition used, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
• Treating” or “treatment” as used herein refers to the treatment of postherpetic neuralgia in a mammal, preferably a human, having postherpetic neuralgia and includes reducing the severity of the postherpetic neuralgia and/or alleviating the postherpetic neuralgia for a period of time following the administration, preferably periodic administration of a topical pharmaceutical composition of the invention.
• the present invention provides methods of treating postherpetic neuralgia in a mammal, preferably a human, wherein the methods comprise administering, preferably periodically administering, to the affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of a spiro-oxindole compound.
• a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of a spiro-oxindole compound.
• the topical pharmaceutical compositions of the invention are suitable for application to the skin of a mammal, preferably a human, and can be in the form of an ointment, a foam, a cream, a lotion, a gel, a liniment or other spreadable semi-liquid preparation.
• a topical pharmaceutical composition of the invention is in the form of an ointment.
• a topical pharmaceutical composition of the invention is in the form of a cream.
• a topical pharmaceutical composition of the invention is in the form of a liniment.
• a topical pharmaceutical composition of the invention is in the form of a lotion.
• a topical pharmaceutical composition of the invention is in the form of a gel.
• a topical pharmaceutical composition of the invention is in the form of a spreadable semi-liquid preparation.
• topical pharmaceutical compositions utilized in the methods of the invention are prepared as disclosed in U.S. Published Patent Application No. 2013/0143941 A1, the relevant disclosure of which is incorporated in full by reference herein.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein the excipients are selected from one or more solvents, optionally from one or more penetration enhancing agents, optionally from one or more stiffening agents, optionally from one or more ointment bases, and optionally one or more antioxidants.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition
• a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and two or more excipients, preferably pharmaceutically acceptable excipients, wherein the excipients are selected from one or more solvents, optionally from one or more penetration enhancing agents, optionally from one or more stiffening agents, optionally from one or more ointment bases, and optionally from one or more antioxidants.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition
• a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and two or more excipients, preferably pharmaceutically acceptable excipients, wherein the excipients are selected from one or more solvents, from one or more penetration enhancing agents, from one or more stiffening agents, from one or more ointment bases, and optionally from one or more antioxidants.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition
• a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein one of the excipients is a solvent selected from polyethylene glycol, diethylene glycol monoethyl ether, polysorbates, alcohols, carpylocaproyl macrogolglycerides, caprylic/capric triglyceride, fatty acid esters, diethyl sebacate, propylene glycol monocaprylate, propylene glycol laurate, mono diglycerides, glyceryl monocaprylate, medium chain triglycerides, hexylene glycol, glyceryl monooleate, 1,2-pentanediol, octyldodecanol, glyceryl mono-linoleate, glycerol o
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition
• a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein one of the excipients is a penetration enhancing agent selected from polyoxyl glycerides (Labrasol®), ethanol, propylene glycol laurate, diethyl sebacate, dimethyl sulfoxide, decylmethylsulfoxide, laurocapram, pyrrolidones, surfactants, alcohols, oleic acid, polyethylene glycol, diethylene glycol monoethyl ether, fatty acid esters or Transcutol® P.
• Labrasol® polyoxyl glycerides
• ethanol propylene glycol laurate
• diethyl sebacate dimethyl sulfoxide
• decylmethylsulfoxide laurocapram
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein one of the excipients is a stiffening agent selected from stearyl alcohol, carbopols, dimethicone or polymers.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein one of the excipients is an ointment base selected from polyethylene glycols.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition
• a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein one of the excipients is optionally an antioxidant selected from butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, flavinoid, glutathione, ascorbic acid and esters, dimethyl sulfoxide, or chelating agents.
• an antioxidant selected from butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, flavinoid, glutathione, ascorbic acid and esters, dimethyl sulfoxide, or chelating agents.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein each excipient is present in a concentration of from about 0.01% w/w to about 99% w/w.
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, preferably pharmaceutically acceptable excipients, wherein a first excipient is a solvent present at a concentration of from about 30% w/w to about 70% w/w, a second excipient is a penetration enhancing agent present in a concentration of from about 2% w/w to about 25% w/w, a third excipient is a penetration enhancing agent present in a concentration of from about 1% w/w to about 10% w/w, a fourth excipient is a penetration enhancing agent present in a concentration of from about 1% w/w to about 25% w/w, a fifth excipient is a stiffening agent present in a concentration of from about 0.1% w/w to about 10% w/w, a sixth excipient is an antioxidant present in a concentration of from about 0.0
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients, wherein a first excipient is a solvent present at a concentration of from about 45% w/w to about 55% w/w, a second excipient is a penetration enhancing agent present in a concentration of from about 5% w/w to about 15% w/w, a third excipient is a penetration enhancing agent present in a concentration of from about 2.5% w/w to about 7.5% w/w, a fourth excipient is a penetration enhancing agent present in a concentration of from about 2.5% w/w to about 7.5% w/w, a fifth excipient is a stiffening agent present in a concentration of from about 0.1% w/w to about 7.5% w/w, a sixth excipient is optionally an antioxidant present in a concentration of from about 0.05% w
• topical pharmaceutical compositions utilized in the methods of the invention is a topical pharmaceutical composition
• a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, and one or more excipients selected from a solvent selected from PEG 400 or PEG 3350; one or more penetration enhancing agents selected from Transcutol® P, oleyl alcohol or isopropyl myristate; a stiffening agent selected from stearyl alcohol; an ointment base selected from PEG 400 or PEG 3350; and optionally an antioxidant selected from butylated hydroxytoluene.
• a further embodiment is a topical pharmaceutical composition
• a therapeutically effective amount of the spiro-oxindole compound wherein PEG 400 is present in a concentration from about 30% w/w to about 70% w/w, Transcutol® P is present in a concentration from about 2% w/w to about 25% w/w, oleyl alcohol is present in a concentration from about 1% w/w to about 10% w/w, isopropyl myristate is present in a concentration from about 1% w/w to about 25% w/w, stearyl alcohol is present in a concentration from about 0.1% w/w to about 10% w/w, BHT is optionally present in a concentration from about 0.01% w/w to about 2% w/w, and PEG 3350 is present in a concentration from about 10% w/w to about 50% w/w.
• a further embodiment is a topical pharmaceutical composition comprising a therapeutically effective amount of the spiro-oxindole compound, wherein PEG 400 is present in a concentration from about 45% w/w to about 55% w/w, Transcutol® P is present in a concentration from about 5% w/w to about 15% w/w, oleyl alcohol is present in a concentration from about 2.5% w/w to about 7.5% w/w, isopropyl is myristate present in a concentration from about 2.5% w/w to about 7.5% w/w, stearyl alcohol is present in a concentration from about 0.1% w/w to about 7.5% w/w, BHT is optionally present in a concentration from about 0.05% w/w to about 1% w/w, and PEG 3350 is present in a concentration from about 15% w/w to about 30% w/w.
• PEG 400 is present in a concentration from about 45% w/w to about 55%
• a further embodiment is wherein the spiro-oxindole compound is present in the topical pharmaceutical composition at a concentration from about 0.1% w/w to about 10% w/w.
• a further embodiment is wherein the spiro-oxindole compound is present in the topical pharmaceutical composition at a concentration from about 2% w/w to about 8% w/w.
• the topical pharmaceutical compositions utilized in the methods of the invention comprise 2% to 8% (w/w) of the spiro-oxindole compound; 45% to 55% (w/w) PEG 400; 5% to 15% (w/w) Transcutol® P; 2.5% to 7.5% (w/w) oleyl alcohol; 2.5% to 7.5% (w/w) isopropyl myristate; 0.1% w/w to 7.5% (w/w) stearyl alcohol; 0.05% to 1% (w/w) butylated hydroxytoluene; and 15% to 30% (w/w) PEG 3350.
• the topical pharmaceutical compositions are in ointment form.
• a topical pharmaceutical composition utilized in the methods of the invention comprises 2.0% (w/w) of the spiro-oxindole compound; 52.9% (w/w) PEG 400; 10% (w/w) Transcutol® P; 5% (w/w) oleyl alcohol; 5% (w/w) isopropyl myristate; 5% (w/w) stearyl alcohol; 0.1% (w/w) butylated hydroxytoluene; and 20% (w/w) PEG 3350.
• This pharmaceutical composition is referred to herein as the “2% ointment”, the “2% pharmaceutical composition of the invention” or the “2% Test Pharmaceutical Composition”.
• another topical pharmaceutical composition utilized in the methods of the invention comprises 4.0% (w/w) of the spiro-oxindole compound; 50.9% (w/w) PEG 400; 10% (w/w) Transcutol® P; 5% (w/w) oleyl alcohol; 5% (w/w) isopropyl myristate; 5% (w/w) stearyl alcohol; 0.1% (w/w) butylated hydroxytoluene; and 20% (w/w) PEG 3350.
• This pharmaceutical composition is referred to herein as the “4% ointment”, the “4% pharmaceutical composition of the invention” or the “4% Test Pharmaceutical Composition”.
• another topical pharmaceutical composition utilized in the methods of the invention comprises 8.0% (w/w) of the spiro-oxindole compound; 46.9% (w/w) PEG 400; 10% (w/w) Transcutol® P; 5% (w/w) oleyl alcohol; 5% (w/w) isopropyl myristate; 5% (w/w) stearyl alcohol; 0.1% (w/w) butylated hydroxytoluene; and 20% (w/w) PEG 3350.
• This pharmaceutical composition is referred to herein as the “8% ointment”, the “8% pharmaceutical composition of the invention” or the “8% Test Pharmaceutical Composition”.
• the active ingredient of the topical pharmaceutical compositions utilized in the methods of the invention is the spiro-oxindole compound having the following formula:
• the above spiro-oxindole compound is a potent, voltage-gated sodium channel (Na V ) blocker developed for the treatment of various pain indications, including neuropathic and nociceptive pain.
• Na V voltage-gated sodium channel
• the block of certain neuronal Na V s has been demonstrated as a means for treating pain and continues to offer an approach for developing novel analgesics.
• the block of Na V 1.3, Na V 1.7 and Na V 1.8 have the most clinical and/or non-clinical evidence to date in supporting analgesic use.
• Na V 1.3 is expressed primarily in the central nervous system in neonatal animals and at low levels throughout the body in adults (Raymond, C. K., et al., J. Biol. Chem . (2004), 279(44):46234-41). It has been demonstrated to have its expression upregulated in the dorsal horn sensory neurons of rats after nervous system injury (Hains, B. D., et al., J. Neurosci . (2003), 23(26):8881-92). Many experts in the field have considered Na V 1.3 as a suitable target for pain therapeutics because its expression is induced by nerve injury (Lai, J., et al., Curr. Opin. Neurobiol . (2003), (3):291-72003; Wood, J.
• Na V 1.7 is expressed primarily in the peripheral nervous system in both sensory and sympathetic neurons (Raymond, C. K., et al., op. cit.).
• Loss-of-function mutations in SCN9A (the gene encoding the alpha subunit of the Na V 1.7 sodium channel) cause a human condition known as congenital indifference to pain characterized by an inability to perceive pain (Cox, J. J., et al., Nature (2006), 444:894-98; Goldberg, Y. P., et al., Clin Genet (2007), 71:311-9).
• Gain-of-function mutations in SCN9A are associated with inherited erythromelalgia (IEM) (Drenth, J.
• Na V 1.8 is predominately in the dorsal root ganglia (DRG) (Raymond, C. K., et al., op. cit.).
• DRG dorsal root ganglia
• the upstroke of the action potential in sensory neurons from DRG is primarily carried by current through Na V 1.8, so that block of this current is likely to block pain responses (Blair, N. T. and Bean, B. P., J. Neurosci. 22: 10277-90).
• knock-down of Na V 1.8 in rats has been achieved by using antisense DNA or small interfering RNAs and virtually complete reversal of neuropathic pain was achieved in the spinal nerve ligation and chronic constriction injury models.
• Topical formulations comprising the spiro-oxindole compound of the invention have demonstrated activity in a variety of nonclinical pain models including the chronic sciatic nerve constriction (chronic constriction injury [CCI]) or Bennett model of neuropathic pain, and the complete Freund's adjuvant (CFA) model of inflammatory pain.
• CCI chronic sciatic nerve constriction injury
• CFA complete Freund's adjuvant
• topical administration of a pharmaceutical composition of the invention provided analgesic relief superior to current marketed topical therapeutics such as lidocaine and diclofenac.
• topical 8% pharmaceutical composition of the invention comprising the spiro-oxindole compound were obtained at a mean plasma concentration (0.32 ng/mL) that was 120-fold lower than the mean plasma concentration observed at the minimum effective dose of an oral pharmaceutical composition comprising the spiro-oxindole compound in this same model.
• a dose-response was observed and the dose associated with pain relief ranged from a minimum effective dose of 2% (w/w) of the spiro-oxindole compound with the greatest effect seen at the highest dose tested of 8% (w/w) of the spiro-oxindole compound.
• the analgesic effect of a topical formulation of the spiro-oxindole compound in these animal models is considered to be due to a local effect rather than a systemic effect.
• micromolar concentrations of the spiro-oxindole compound of the invention were detected, surprisingly, in the synovial membrane tissue of the joint, despite very low (i.e., nanomolar) plasma concentrations.
• the results of this study were surprising in that they demonstrated that the spiro-oxindole compound of the invention, when topically administered, has an excellent ability to penetrate into the target joint tissue, particularly the synovial membrane of the joint, at concentration levels higher than expected with minimal or negligible systemic exposure after administration.
• the fact that the spiro-oxindole compound of the invention was previously found to be highly protein bound in human, monkey, dog, minipig, rat and mouse plasma at the 0.1, 1.0 and 10 ⁇ M concentrations (97.4% to 99.8%) may explain its ability to penetrate into joint tissue, particularly the synovial membrane of the joint, at concentration levels higher than expected with minimal or negligible systemic exposure.
• the spiro-oxindole compound may have potent local effects in terms of treating postherpetic neuralgia, like the nonselective sodium channel blocker lidocaine.
• the spiro-oxindole compounds has been designed to selectively block activity in the Na V 1.7 channel, which is believed to be the most important sodium channel contributing to spontaneous and hyperactive discharges emanating from peripheral nociceptive neurons.
• spiro-oxindole compounds has efficacy in several classical neuropathic pain models, with comparable efficacy to gabapentin in the chronic constriction injury (CCI) model and superior efficacy to 5% lidocaine in a topical streptozotocin-induced diabetic neuropathic pain model.
• CCI chronic constriction injury
• Topical formulations comprising the spiro-oxindole compound have been studied in a 2-period crossover trial (each period lasting 3 weeks) in 70 postherpetic neuralgia patients who received one or more doses of the compositions as described in more detail below in the Biological Examples. Although the trial did not meet the primary endpoint (change in mean daily pain score during the last week compared to baseline as measured by the Likert Numeric Rating Scale (NRS)), a significantly larger percentage of patients with 50% reduction in pain were seen during the treatment period in the efficacy evaluable and per protocol (PP) analysis groups.
• a further clinical trial designed to further evaluate the efficacy of pharmaceutical compositions of the spiro-oxindole compound in treating postherpetic neuralgia in a larger parallel-group study design, is described in more detail below in the Biological Examples.
• a topical formulation of the spiro-oxindole compound of the invention has also been tested in a clinical study for erythromelalgia and was well tolerated by the patients.
• the methods of the invention are directed to the administration, preferably periodic administration, of a topical pharmaceutical composition of the invention comprising one or more excipients and a therapeutically effect amount of the spiro-oxindole compound to a mammal, preferably a human, as needed to reduce the severity of postherpetic neuralgia and/or to alleviate postherpetic neuralgia with minimal or negligible systemic exposure.
• the topical pharmaceutical compositions of the invention may be administered as one-time single dose.
• the topical pharmaceutical compositions of the invention are periodically administered.
• a periodic administration of a topical pharmaceutical composition of the invention will include an initial application of a topical pharmaceutical composition of the invention followed by a pre-determined time period and then the topical pharmaceutical composition of the invention is applied a second time to the same area and then followed by the same pre-determined time period and so forth for a specified duration of time.
• the pre-determined time period can be from about 4 hours to about 24 hours.
• a topical pharmaceutical composition utilized in the methods of the invention is periodically administered to a mammal, preferably a human, having postherpetic neuralgia to the affected skin area once (qd), twice (bid), three (tid) or four (qid) times a day as needed to reduce the severity of the postherpetic neuralgia and/or to alleviate the postherpetic neuralgia.
• a pharmaceutical composition of the invention is periodically administered once a day (every 24 hours) as needed (i.e., an effective amount of the pharmaceutical composition is topically applied to the affected skin area when postherpetic neuralgia is present).
• the pharmaceutical composition is topically administered twice a day (every 12 hours) as needed.
• the pharmaceutical composition is topically administered three times a day (every 8 hours) as needed. In another embodiment, the pharmaceutical composition is topically administered four times a day (every 6 hours) as needed. Preferably, the pharmaceutical composition is topically administered once or twice a day.
• the specified duration of time for the periodic administration of a topical pharmaceutical composition of the invention is intended to be as long as needed to alleviate or substantially relieve the pain.
• the duration of the periodic administration of a topical pharmaceutical compositions of the invention is from about 1 week to about 6 months, more preferably from about 1 month to 4 months, even more preferably about 3 months.
• the dose volume of a pharmaceutical composition utilized in the methods of the invention which is topically administered to the affected skin area of the mammal, preferably a human is from about 1.0 ⁇ L/cm 2 to about 9.0 ⁇ L/cm 2 , preferably from about 1.0 ⁇ L/cm 2 to about 4.0 ⁇ L/cm 2 of skin, more preferably about 3.0 ⁇ L/cm 2 .
• the therapeutically effective amount of each dose of a topical pharmaceutical composition of the invention is from about 500 mg to about 2000 mg, preferably from about 500 mg to about 1500 mg, more preferably from about 750 mg to about 1200 mg, most preferably about 1200 mg per each administration to the affected skin area.
• the therapeutically effective amount of the spiro-oxindole compound in each dose of a topical pharmaceutical composition of the invention is from about 10 mg to about 160 mg, preferably about 24 mg in a 2% pharmaceutical composition of the invention at 3.0 ⁇ L/cm 2 dose volume, 48 mg in a 4% pharmaceutical composition of the invention at 3.0 ⁇ L/cm 2 dose volume, or 96 mg in a 8% pharmaceutical composition of the invention at 3.0 ⁇ L/cm 2 dose volume.
• Topical administration of a pharmaceutical composition of the invention can be effected by any method commonly known to those skilled in the art. These methods include, but are not limited to, incorporation of a pharmaceutical composition of the invention into foams, creams, gels, ointments, liniments, transdermal patches or other topical formulations and delivery systems.
• Topical administration of a pharmaceutical composition of the invention may be performed by a medical professional or by the patient.
• the affected skin area to which the pharmaceutical composition of the invention is to be administered is first cleansed, for example using an astringent, such as a standard commercial antiseptic or alcohol, or water, preferably sterile water.
• the affected skin area is then allowed to dry, and the pharmaceutical composition of the invention is applied onto the affected skin area and rubbed until all the pharmaceutical composition has been absorbed or no residue remains on the skin.
• the recipients of topical administration of a pharmaceutical composition of the invention can be any vertebrate animal, such as mammals.
• the preferred recipients are mammals of the Orders Primate (including humans, apes and monkeys), Arteriodactyla (including horses, goats, cows, sheep, and pigs), Rodenta (including mice, rats, rabbits, and hamsters), and Carnivora (including cats, and dogs).
• the preferred recipients are turkeys, chickens and other members of the same order. The most preferred recipients are humans.
• one aspect of the invention is a method of treating postherpetic neuralgia in a mammal, wherein the method comprises administering, preferably periodically administering, to the affected skin area of the mammal a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of the spiro-oxindole compound described above in the Summary of the Invention.
• the method results in minimal or negligible systemic exposure of the spiro-oxindole compound.
• the method results in a greater concentration of the spiro-oxindole compound in the affected skin area than the concentration of the spiro-oxindole compound in the plasma of the mammal.
• another aspect of the invention is a method of locally treating postherpetic neuralgia in a mammal with a minimal or negligible systemic exposure, wherein the method comprises increasing the concentration of the spiro-oxindole compound described above in the Summary of the Invention to a therapeutically effective amount in the affected skin area in the mammal by administering, preferably periodically administering, to the affected skin area a topical pharmaceutical composition comprising one or more excipients and a therapeutically effective amount of the spiro-oxindole compound.
• the pharmaceutical composition comprises 2% to 8% (w/w) of the spiro-oxindole compound.
• the pharmaceutical composition comprises 2% to 8% (w/w) of the spiro-oxindole compound; 45% to 55% (w/w) PEG 400; 5% to 15% (w/w) Transcutol® P; 2.5% to 7.5% (w/w) oleyl alcohol; 2.5% to 7.5% (w/w) isopropyl myristate; 0.1% w/w to 7.5% (w/w) stearyl alcohol; 0.05% to 1% (w/w) butylated hydroxytoluene; and 15% to 30% (w/w) PEG 3350.
• the pharmaceutical composition comprises 2.0% (w/w) of the spiro-oxindole compound; 52.9% (w/w) PEG 400; 10% (w/w) Transcutol® P; 5% (w/w) oleyl alcohol; 5% (w/w) isopropyl myristate; 5% (w/w) stearyl alcohol; 0.1% (w/w) butylated hydroxytoluene; and 20% (w/w) PEG 3350.
• the pharmaceutical composition comprises 4.0% (w/w) of the spiro-oxindole compound; 50.9% (w/w) PEG 400; 10% (w/w) Transcutol® P; 5% (w/w) oleyl alcohol; 5% (w/w) isopropyl myristate; 5% (w/w) stearyl alcohol; 0.1% (w/w) butylated hydroxytoluene; and 20% (w/w) PEG 3350.
• the pharmaceutical composition comprises 8.0% (w/w) of the spiro-oxindole compound; 46.9% (w/w) PEG 400; 10% (w/w) Transcutol® P; 5% (w/w) oleyl alcohol; 5% (w/w) isopropyl myristate; 5% (w/w) stearyl alcohol; 0.1% (w/w) butylated hydroxytoluene; and 20% (w/w) PEG 3350.
• the periodic administration is once a day, twice a day, three times a day or four times a day.
• the periodic administration is twice a day.
• the periodic administration is once a day.
• the topical pharmaceutical composition is administered to the affected skin area in a dose volume of from about 1.0 ⁇ L/cm 2 to about 9.0 ⁇ L/cm 2 .
• the topical pharmaceutical composition is administered to the affected skin area in a dose volume of from about 1.0 ⁇ L/cm 2 to about 4.0 ⁇ L/cm 2 .
• the topical pharmaceutical composition is administered to the affected skin area in a dose volume of 3.0 ⁇ L/cm 2
• the therapeutically effective amount of a topical pharmaceutical composition of the invention is from about 500 mg to about 2000 mg per each administration, preferably each periodic administration, to the affected skin are.
• the therapeutically effective amount of a topical pharmaceutical composition of the invention is about 1200 mg per each administration, preferably each periodic administration, to the affected skin area.
• the therapeutically effective amount of the topical pharmaceutical composition of the invention is effective in reducing the severity of the postherpetic neuralgia or alleviating the postherpetic neuralgia.
• the mammal is human.
• the administration, preferably periodic administration, of the topical pharmaceutical composition is effective in reducing a daily average postherpetic neuralgia intensity or severity in the affected skin area in the human when compared to baseline postherpetic neuralgia intensity or severity.
• the administration, preferably periodic administration, of the topical pharmaceutical composition of the invention is effective in reducing the postherpetic intensity or severity as assessed by a Linkert Numeric Rating Scale (NRS) score, a Neuropathic Pain Symptom Inventory (NPSI) score, a Daily Sleep Interference Scale (DSIS) score, a Neuropathic Pain Impact on Quality of Life (NePIQoL) score and/or a Patient Global Impression of Change (PGIC) score.
• NRS Linkert Numeric Rating Scale
• NPSI Neuropathic Pain Symptom Inventory
• DSIS Daily Sleep Interference Scale
• NePIQoL Neuropathic Pain Impact on Quality of Life
• PGIC Patient Global Impression of Change
• the administration, preferably periodic administration, of the topical pharmaceutical composition of the invention is effective in reducing the postherpetic neuralgia intensity or severity by 30% when compared to the baseline postherpetic neuralgia intensity or severity.
• the topical pharmaceutical composition of the invention is effective in reducing the postherpetic neuralgia intensity or severity by 50% when compared to the baseline postherpetic neuralgia intensity or severity.
• the methods of the invention may be usefully combined with the administration of one or more other therapeutic agents or as any combination thereof, in the treatment of postherpetic neuralgia.
• the methods of the invention may be utilized in the treatment of postherpetic neuralgia simultaneously, sequentially or separately in combination with other therapeutic methods for the administration of other agents, including, but not limited to:
• the one or other therapeutic agents utilized in the combination therapy of the invention may be administered to the mammal, preferably a human, by any route known to one skilled in the art, e.g., orally, topically, peripherally, intravenously, nasally, etc. and in any form.
• a method of the invention may therefore be utilized in treating postherpetic neuralgia in a mammal by administering, preferably periodically administering, a topical pharmaceutical composition of the invention as defined above in the Summary of the Invention and one or more therapeutic agents.
• the one or other therapeutic agent is a non-opioid analgesics, such as acetaminophen (e.g., TYLENOL®) and salicylates (e.g., aspirin).
• kits for using the methods of the invention.
• the kits contain a pharmaceutical composition of the invention and instructions for the use of the pharmaceutical composition for treating postherpetic neuralgia.
• a commercial kit will contain one or more unit doses of the pharmaceutical composition of the invention.
• any such composition which is light and/or air sensitive may require additional special packaging and/or instructions.
• packaging may be used which is opaque to light, and/or sealed from contact with ambient air.
• the animals also received an intravenous dose of midazolam on Day 0 and again on Day 20 and blood samples were collected for analysis of plasma midazolam concentrations for investigation of CYP3A4 induction or inhibition.
• Concentrations of radioactivity were measured in plasma, tissues and excreta by liquid scintillation analysis, concentrations of unchanged spiro-oxindole compound in plasma and selected tissues were determined by an LC-MS/MS bioanalytical method. Attempts to separate radioactive components present in plasma, liver and excreta using HPLC with radioactivity detection were unsuccessful due to low radioactivity levels in these samples.
• Midazolam was administered on Days 0 and 20 to 3 male minipigs by bolus intravenous injection at a dose level 0.5 mg/kg.
• a 8% test pharmaceutical composition of the invention was administered topically as an ointment to a clean shaven area of 209-259 cm 2 (6% of total body surface area) on the back of the male minipigs at a dose level of about 70 mg ointment/kg.
• the 8% test pharmaceutical composition comprised the following:
• [ 14 C]-spiro-oxindole composition was administered topically as an ointment for a single dose at a dose level of ca 70 mg spiro-oxindole compound equivalents ointment/kg onto the same dose site area of skin.
• the [ 14 C]-spiro-oxindole composition was prepared as follows:
• Radioactivity were measured in plasma, tissues and excreta by liquid scintillation analysis, concentrations of unchanged drug in plasma and selected tissues were determined by an LC-MS/MS bioanalytical method. Attempts to separate radioactive components using HPLC with radioactivity detection present in plasma, liver and excreta were unsuccessful due to low radioactivity levels in samples submitted for further analysis.
• [ 14 C]-spiro-oxindole compound (specific activity 55 mCi/mmol ⁇ 128 ⁇ Ci/mg) was supplied as a solution and stored at ca ⁇ 20° C. in the absence of moisture and light.
• Non-radiolabelled spiro-oxindole compound was supplied as a solid and stored at room temperature.
• Non-radiolabelled 8% test pharmaceutical composition of the invention as an ointment was supplied and stored at room temperature.
• the radiochemical purity of [ 14 C]-spiro-oxindole compound was determined by high performance liquid chromatography (HPLC) with on-line radioactivity detection at the study center.
• the radiochemical purity of the test substance provided was less then 97%, it was repurified at the study center prior to the start of the study and stored at ca ⁇ 20° C. in the absence of moisture and light.
• the radiochemical purity of the repurified batch was 99.2% by HPLC prior to the start of the study.
• the minipigs were allowed an acclimatization period of approximately 3 weeks prior to treatment with the test substance.
• the animals were group-housed in indoor pens except during the period of sample collection following intravesical dose administration when they were housed individually in stainless-steel metabolism cages equipped with wire mesh floors and plastic netting below to allow the separate collection of urine from faeces. Whilst housed within the indoor pens, the animals were provided with cereal straw bedding and soiled bedding was changed daily.
• the rooms in which the minipigs were housed were well ventilated with regular air changes, and lit using artificial light, which was controlled to provide an alternating 12-hour light/dark cycle.
• the ambient air temperature in the animal housing unit was in the range of 15-24° C., and the relative humidity between 40% and 70%; both temperature and humidity were continuously monitored and automatically recorded.
• the minipigs were routinely observed for behavioural changes, and any indications of ill health or reaction to treatment.
• the animals were observed immediately after dosing, again within 2 hours of completion of dosing the study group/phase and on at least one other occasion towards the end of the working day.
• the animals were observed on at least one occasion, i.e., during the initial animal check procedure.
• Midazolam doses were administered by bolus intravenous administration at a target dose level of 0.5 mg/kg and were quantified using nominal concentration of midazolam provided and the volume administered to each animal.
• test formulations were applied with foil and spread using nitrile gloves to form a thin uniform layer to the treatment site.
• the dose site remained non-occluded during the 20 days of study composition applications (8% test pharmaceutical composition) but was semi-occluded immediately after the radiolabelled dose application on Day-21 using a tubular elastic net bandage secured in place with a dressing retention tape.
• the 8% test pharmaceutical composition of the invention application was quantified from the weight of test formulation applied over the treatment area.
• [ 14 C]-spiro-oxindole composition doses were applied in the same manner over the same dose site area as the 8% test pharmaceutical composition and covered with dressings.
• the radioactive dose administered to each animal was calculated from the weight of radiolabelled composition supplied and the measured radioactivity concentration. Any residual radiolabelled material remaining on the treatment foil was not quantified so was not included in the calculation of dose administered to each animal.
• a blood sample (ca 2 mL) was collected by venepuncture from each minipig and delivered into K 2 EDTA anticoagulant tubes.
• the blood was centrifuged (ca 2000 ⁇ ‘g’ for 10 minutes at ca 4° C.) to obtain the plasma which was transferred into clean polypropylene tubes, divided into two portions and stored at ca ⁇ 20° C.; blood cells were discarded.
• Urine was collected (into containers cooled in solid CO 2 ) from all minipigs overnight prior to dosing the first Midazolam dose and [ 14 C]-spiro-oxindole composition dose, and during 0-6 and 6-24 hours postdose. Feces were collected separately overnight prior to dosing and during 0-24 hours after the [ 14 C]-spiro-oxindole composition dose. After collection of the final excreta samples, cages were first washed with water (ca 1 Liter) and then methanol (ca 1 Liter), and the washings were retained for radioactivity analysis.
• the semi-occlusive dressings were removed and the dose area cleansed with copious volumes of warm dilute soap solution and dabbed dry with the minimum amount of paper medical wipe. All dressings, washings and wipes were retained for radioactivity measurement.
• the animals were then sacrificed (pentobarbitone overdose), the stratum corneum at the dose site were removed by tape-stripping (10-20 strips) and retained for radioactivity analysis.
• the dose site was then excised from the carcass and divided into two approximately equal portions. For one portion, the epidermis was separated from the underlying dermis by transferring each skin sample to a foil boat and heating in a waterbath at 60° C. for approximately 20 minutes. The second portion was immediately attached to cork discs with embedding medium and snap frozen in isopentane cooled with liquid nitrogen. These mounted and frozen samples were stored at ca ⁇ 70° C. until taken for microautoradiography.
• Adrenal gland Pituitary Aorta Prostate Bile from the gall bladder
• Salivary gland Bone Sciatic nerve Bone marrow Synovial membrane (knee joint) Brain Skin (remote from the dose site) CSF Skin (from the dose site after Epididymis washing and tape stripping)
• Eye Spinal cord Fat (white) Spleen Fat (brown)
• Testis Heart Thymus Kidney Thyroid Lacrimal gland
• Urinary bladder Liver Vena cava Lungs Stomach wall Lymph nodes Stomach content Muscle (remote from dose site) Small intestine wall Muscle (underlying dose site) Small intestine content Pancreas Large intestine wall Large intestine content
• the urinary bladder from each animal was rinsed with saline and the washings discarded. Each section of the gastrointestinal tract wall was washed to remove contents (which were retained for analysis) prior to analysis. Remaining carcasses were discarded.
• Concentrations of radioactivity were measured in plasma, tissues and excreta by liquid scintillation analysis, concentrations of unchanged spiro-oxindole compound in plasma and selected tissues were determined by an LC-MS/MS bioanalytical method. Attempts to separate radioactive components present in plasma, liver and excreta using HPLC with radioactivity detection were unsuccessful due to low radioactivity levels in these samples.
• Concentrations of the spiro-oxindole compound in plasma were above the limit of quantification (>0.5 ng/mL) at predose on Day 2 (i.e., approximately 24 hours after a single dermal dose of 8% test pharmaceutical composition of the invention) when they measured a mean of 1.43 ng/mL, then increased steadily until predose on Day 14 to a mean of 5.86 ng/mL.
• mean spiro-oxindole compound concentrations were 3.33 ng/mL, which were similar to concentrations observed on Day 14, indicating that steady-state was achieved between Days 14 and 21.
• mean plasma concentrations of spiro-oxindole compound increased and were maximal at 8 hours post dose, then declined and at 24 hours post dose, mean plasma concentrations were 6.06 mg/mL, which was significantly similar to concentrations observed at predose on Day 21.
• mean plasma radioactivity concentrations were generally below the limit of quantification until 8 hours after administration of the radiolabelled ointment on Day 21 when they measured 11.7 ng/mL. Thereafter, mean plasma radioactivity concentrations increased until the final sampling time (24 hours post dose).
• Tissue radioactivity concentrations were generally below the limit of quantification (ca 12-25 ng equivalents spiro-oxindole compound/g) in the majority of tissues analysed.
• mean radioactivity concentrations ng equivalents spiro-oxindole compound/g were maximal in skin from the dose site (25500), gall bladder contents (4870), fatty tissues (273 [abdominal], 100 [brown]), bone marrow (154), muscle underlying the dose site (142) and skin remote from the dose site (111).
• Concentrations of the spiro-oxindole compound were also measured in selected tissues and were maximal in skin from the dose site (1860 ng/g), white fat (53.8 ng/g), heart (17.5 ng/g) and liver (11.3 ng/g). The corresponding total radioactivity in these tissues were 25500, 273, 18.5 and 74.9 ng equiv spiro-oxindole compound/g, respectively.
• Results of microautoradiography of skin samples removed from the dose site after the final dermal dose of [ 14 C]-spiro-oxindole compound ointment indicated localization of spiro-oxindole compound-related material in the epidermis, dermis and hair follicles. Greatest concentrations were found at the epidermis and dermo-epidermal junction, and at the hair follicles, particularly the hair follicle bulbs.
• a full pharmacokinetic sampling was performed on Day 17 (post am dosing) at the following time points: 1, 2, 4, 8 and 12 hr.
• Day 18 blood was collected prior to euthanasia, each pig was humanely euthanized and dorsal skin and muscle, liver, kidney, heart, lung, brain, intestine, fat, ovaries, urinary bladder, sciatic nerve, and skin, muscle, synovial membrane, and synovial fluid from all 4 joints (2 treated, left carpus and hock, and 2 untreated, right carpus and hock) was collected.
• Doses were calculated by measuring the joint circumference and joint width (to include ⁇ 2 cm above and below the joint) to calculate the total surface area for each individual dose.
• Group 1 received a 2% pharmaceutical composition of the invention and the dose volume for Group 1 was calculated using the total surface area and the designated dose volume of 3 ⁇ L/cm 2 .
• the total dose volume was then converted from ⁇ L to mL to estimate the dose weight in grams, based on the composition density of 1 g/cm 3 .
• the dose volume was calculated using the total surface area and the designated dose volume of 3 ⁇ L/cm 2 (Groups 2, 3 and 5) or 1 ⁇ L/cm 2 (Group 4).
• the total dose volume was then converted from ⁇ L to mL to estimate the dose length in centimeters of a ribbon of the pharmaceutical composition when squeezed from a glaminate tube onto a metal metric ruler, based on the composition length-weight relationship of 1 cm of pharmaceutical composition being equal to 0.5 g of the composition (diameter of the tube opening was 0.87 cm).
• test pharmaceutical compositions were comprised as follows:
• the 2% Test Pharmaceutical Composition was topically administered to the animals of Group 1.
• the 4% Test Pharmaceutical Composition was topically administered to the animals of Group 2.
• the 8% Test Pharmaceutical Composition was topically administered to the animals of Group 3, Group 4 and Group 5.
• test compositions were topically applied an equal distance above and below the center of the joint, i.e., inter-carpal joint space (carpus) and inter-tarsal joint space (hock) of each animal to allow for complete coverage of the joint, including approximately 2 cm above and below the edges of the joint.
• the test composition was applied to the entire circumference of the designated area. All animals were dosed using the same distance above and below each joint center for consistency.
• the dose volume ( ⁇ L/cm 2 ) for the test pharmaceutical compositions was 3.0 ⁇ L/cm 2 for Groups 1, 2, 3 and 5 and 1.0 ⁇ L/cm 2 for Group 4.
• the concentration of the spiro-oxindole compound (in ng/g) in liver tissue of the test animals is shown in Table 6 below:
• the objectives of this study were to compare the safety and efficacy of a pharmaceutical composition of the invention to that of placebo for the relief of postherpetic neuralgia in subjects with postherpetic neuralgia (PHN) and to evaluate the extent of systemic exposure of the spiro-oxindole compound following topical application of the pharmaceutical composition in subjects with postherpetic neuralgia.
• Subjects who qualified for the study after the screening/washout period entered into the first single-blind, placebo run-in period entered into the first single-blind, placebo run-in period.
• the area of application was to cover the most painful skin segments up to 400 cm 2 .
• Subjects recorded their pain score at 4 specific times each day (upon waking, at 12:00 noon ⁇ 1 hour, at 4:00 p.m. ⁇ 1 hour, and at 8:00 p.m. ⁇ 1 hour) and reported these scores using the Medpace ClinTrak Interactive Voice Response System (CTIVRS).
• CTIVRS Medpace ClinTrak Interactive Voice Response System
• the use of any rescue medication 1000 mg acetaminophen every 4 to 6 hours, up to 4000 mg/day was recorded in the rescue medication diary.
• Subjects who reported average daily pain scores on an 11-point Likert Numerical Rating Scale (NRS) for at least 4 days during the first placebo run-in period were eligible for randomization to treatment and entered into Treatment Period 1.
• NRS Likert Numerical Rating Scale
• subjects were randomly assigned (in a 1:1 ratio) to one of the following treatment sequences: investigational product/placebo or placebo/investigational product.
• Subjects received the first specified treatment during Treatment Period 1 and the second specified treatment during Treatment Period 2.
• Treatment Period 1 subjects began a 1-week washout prior to starting the second period of the crossover study. During the washout, subjects did not apply any study medication (placebo or investigational product), but continued to record pain scores using the CTIVRS. The use of any rescue medication was recorded in the rescue medication diary.
• the population for this study included male and female subjects to 80 years of age with persistent pain for more than 6 months from the appearance of herpes zoster rash that was not located on the face, above the hairline of the scalp, and/or in proximity to mucous membranes.
• the investigational product was the 8% Test Pharmaceutical Composition in ointment form as disclosed herein.
• the placebo composition had the same composition as the 8% Test Pharmaceutical Composition except that the spiro-oxindole compound is not present and the amount of PEG400 in the placebo composition is increased by the amount of the spiro-oxindole compound if it were present.
• the placebo composition was identical in appearance to 8% Test Pharmaceutical Composition ointment.
• Subjects applied 8% Test Pharmaceutical Composition or placebo composition twice a day (bid) topically to cover the most painful skin segments up to 400 cm 2 .
• Each subject was assigned to 1 of 4 dose groups based on the size of the affected skin area.
• Subjects were then provided with an application-area specific dosing card, as shown below in Table 7, which clearly indicated the amount of the treatment composition which was to be measure out and applied on each dosing occasion.
• Dose Composition Dose compound (cm 2 ) (mg) (mL) (mg) ⁇ 100 750 0.75 60 101 to 200 1500 1.50 120 201 to 300 2250 2.25 180 301 to 400 3000 3.00 240
• Treatments were supplied as a 50 g supply in 60 mL plastic laminate tubes with a tamper-proof seal.
• Treatments were provided as single tubes of placebo composition for each single-blind, placebo run-in period and in cartons of 3 tubes containing either the 8% Test Pharmaceutical Composition or the placebo composition for each of the 2 Treatment Periods.
• the primary efficacy parameter was change in mean daily pain score from baseline, measured on an 11-point Likert Numeric Rating Scale (NRS), between the last week of 8% Test Pharmaceutical Composition treatment and the last week of placebo treatment for each subject.
• NRS Likert Numeric Rating Scale
• the secondary efficacy parameters included the following:
• the primary efficacy variable was the change in mean daily pain score from baseline to the last week (Week 3) of the Treatment Period.
• Baseline for Treatment Period 1 was the average of the 7 mean daily pain measurements prior to randomization (Visit 3), and baseline for Treatment Period 2 was the average of the 7 mean daily pain measurements prior to Visit 8.
• the primary efficacy analysis was based on the Efficacy Evaluable Population. Supportive and exploratory analyses were carried out for the primary efficacy variable based on the Intent-to-Treat and Per-Protocol Populations.
• the primary efficacy hypothesis was that the mean change in mean daily pain scores from baseline to the end of the Treatment Period would differ between the 8% Test Pharmaceutical Composition treatment and the placebo treatment.
• This hypothesis was tested using a mixed effects analysis of covariance (ANCOVA) model with treatment, period, and treatment sequence as fixed effects, subject within treatment sequence as a random effect, and the baseline pain score as a covariate.
• ANCOVA mixed effects analysis of covariance
• the least-squares means, standard errors, and the 2-tailed 95% confidence intervals for each treatment group were presented.
• the secondary efficacy parameter of change in mean daily pain scores from baseline to Week 1, Week 2, Week 2 with LOCF, Week 3, and over the entire Treatment Period (Weeks 1-3 combined) was analyzed in a similar manner as the primary efficacy variable.
• efficacy variables were summarized using similar methods as for the primary efficacy variable. Efficacy variables were summarized by area of application ( ⁇ 100 cm 2 , 101 cm 2 to 200 cm 2 , 201 cm 2 to 300 cm 2 , and 301 cm 2 to 400 cm 2 ). Other subgroup analyses (such as demographic variables, disease duration, concomitant medication, etc.) for efficacy variables were performed, as needed. An additional analysis was performed in which all pain scores collected during weeks when subject study medication utilization was ⁇ 80% or >125% were excluded.
• NPSI score analysis showed greater decreases in the overall score with the 8% Test Pharmaceutical Composition treatment than with the placebo treatment, but the difference between treatments was not statistically significant.
• PK analyses demonstrated a low systemic exposure with the 8% Test Pharmaceutical Composition and the dosing regimen of the 8% Test Pharmaceutical Composition.
• approximately 70% of subjects had concentration levels of the spiro-oxindole compound above the detectable limit, but these levels were significantly lower than those previously shown to mediate a systemic analgesic effect.
• Low residual plasma concentrations were measured during placebo treatment for some subjects whose first treatment was the 8% Test Pharmaceutical Composition.
• the placebo response was minimal for those subjects who were dosed with placebo in Treatment Period 2 (the investigational product/placebo sequence) with only 1 subject demonstrating a 50% or greater improvement and 3 subjects demonstrating a 30% or greater improvement.
• the 8% Test Pharmaceutical Composition was safe and well tolerated in subjects with postherpetic neuralgia.
• the overall incidence of treatment-emergent adverse events (TEAEs) was 50.8% with placebo treatment and 53.2% with 8% Test Pharmaceutical Composition treatment.
• the overall incidence of study medication-related TEAEs was 30.2% with the placebo treatment and 17.7% with the 8% Test Pharmaceutical Composition treatment.
• SAEs serious adverse events
• an SAE of tooth abscess which occurred during placebo treatment
• an SAE of worsening coronary artery disease which occurred during the 8% Test Pharmaceutical Composition treatment.
• Neither SAE was considered by investigators to be related to study medication.
• This study is designed to evaluate the efficacy of 4 weeks of topical administration of the 4% Test Pharmaceutical Composition and the 8% Test Pharmaceutical Composition of the invention in ointment form compared with placebo for the relief of postherpetic neuralgia as assessed by the change from baseline to week 4 in the weekly average of the daily average Numeric Rating Scale (NRS) scores.
• NRS Numeric Rating Scale
• Nonclinical studies have been completed to characterize the tolerability, toxicity, pharmacokinetics, and efficacy of pharmaceutical compositions comprising the spiro-oxindole compound following dermal application and oral administration.
• the spiro-oxindole compound is a potent Na V blocker active against several Na V subtypes, including those associated with pain signaling.
• Topical 4% Test Pharmaceutical Composition was compared with lidocaine and diclofenac for relief of mechanical allodynia in the streptozotocin-induced neuropathic pain model in rats.
• a single application of 4% Test Pharmaceutical Composition significantly increased the paw withdrawal threshold for the treated paw compared with application of the vehicle.
• the 4% Test Pharmaceutical Composition treatment group showed reversal of mechanical hyperalgesia as assessed by measurement of paw withdrawal threshold for the drug-treated paw, with no significant increase in threshold observed for the diclofenac and lidocaine treatment groups.
• topical 8% Test Pharmaceutical Composition exhibited a degree of efficacy comparable with 25 mg/kg spiro-oxindole compound by oral administration despite systemic plasma exposure of the spiro-oxindole compound (maximum observed concentration [C max ] 3.6 ng/mL) being significantly lower (approximately 20-fold) than that of the oral treatment group. Based on these data, the analgesic effect of topical pharmaceutical composition comprising the spiro-oxindole compound in these animal models is considered to be due to a local rather than a systemic drug effect.
• the spiro-oxindole compound is highly protein bound in rat serum (99.6%) and dog (98.3%) and human (99.4%) plasma.
• In vitro metabolic stability and profiling of 14 C-spiro-oxindole compound demonstrated that spiro-oxindole compound is more stable in human than in animal hepatocytes: human (80%)>dog (61%)>minipig (18%) ⁇ rat (16%).
• a total of 8 metabolites were identified in samples (in vitro and in vivo) from rats, dogs, and humans. All metabolites found in humans were also found in the Good Laboratory Practice (GLP) toxicology species, the rat.
• GLP Good Laboratory Practice
• spiro-oxindole compound Following oral administration of spiro-oxindole compound to humans, spiro-oxindole compound and 3 of its metabolites (M1, M5, and M6) were measurable. A similar metabolic profile was observed following topical administration to humans, albeit at much lower plasma concentrations, except metabolite M1 was not detected following human topical administration.
• CYP450 cytochrome P450
• spiro-oxindole compound may inhibit several CYP450 enzymes including CYP3A4 but may also be a strong inducer of CYP3A4 with an activation potency similar to rifampicin, a known inducer of CYP3A4.
• a drug-drug interaction (DDI) study conducted in dogs with oral administration of the spiro-oxindole compound using intravenous (iv) midazolam as a CYP3A4 substrate revealed no evidence of a DDI at the spiro-oxindole compound plasma concentrations up to 752 ng/mL (i.e., 1.8 ⁇ M).
• the C max was 21 and 20 ng/mL for male and female minipigs, respectively, and their corresponding area under the concentration-time curve from 0 to 24 hours (AUC 0-24 h ) values were 365 and 382 ng ⁇ h/mL, respectively.
• onset and severity of the skin reactions were similar in all dosing regimens regardless of active or vehicle, dose volume, dosing frequency, or dosing interval. Slight to well-defined erythema (grades 1 to 2) first appeared within the first week of treatment (on days 5, 6, or 7) and progressed to moderate/severe erythema (grades 3 to 4) usually about 2 weeks after dosing initiation. The erythema was reversible after a few days of cessation of treatment. When the vehicle ointment was applied in a dose titration manner, the severity of irritation appeared to be reduced and remained at a low grade until the end of treatment (day 47).
• the spiro-oxindole compound was not genotoxic in the standard battery of genotoxicity tests (GLP), including a bacterial reverse mutation assay, an in vitro chromosome aberration assay in cultured human lymphocytes, and an in vivo rat bone marrow micronucleus test.
• GLP genotoxicity tests
• the corresponding C max and AUC 0-24 h values were 1435 ng/mL and 17966 ng ⁇ h/mL, respectively, on day gestation day (GD) 17.
• the NOAEL for embryo-fetal toxicity was 150 mg/kg/day.
• the corresponding C max and AUC 0-24 h values were 3378 ng/mL and 41545 ng ⁇ h/mL, respectively, on GD17.
• Test Pharmaceutical Composition was found to be a mild skin irritant in an acute dermal irritation study in rabbits. However, it was not an irritant in an acute eye irritation study in rabbits.
• the spiro-oxindole compound was not a skin sensitizer in a mouse local lymph node assay and did not show phototoxicity potential in either in vitro or in vivo assays.
• topically administered spiro-oxindole compound has been evaluated in 3 clinical studies: a Phase 1 study in healthy subjects, a Phase 2a study in patients with postherpetic neuralgia, and a Phase 2a study in patients with inherited erythromelalgia (IEM). Eighty-nine subjects (20 healthy subjects, 70 PHN patients, and 7 IEM patients) received multiple applications of 8% Test Pharmaceutical Composition.
• Test Pharmaceutical Composition is currently underway in a Phase 2 study in patients with osteoarthritis (OA) of the knee, and in a Phase 1 dose-escalation study in healthy volunteers. Final data are not yet available from these ongoing studies.
• Oral spiro-oxindole compound has been evaluated in 3 clinical studies: a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study, a Phase 2a study in patients with pain following third molar extractions, and a Phase 2a study in patients with IEM.
• SAD Phase 1 single ascending dose
• MAD multiple ascending dose
• Topical administration of the spiro-oxindole compound results in minimal to negligible systemic exposure to the spiro-oxindole compound.
• the plasma concentrations of the spiro-oxindole compound disclosed in this paragraph are maximum individual (not group mean) values.
• 8% Test Pharmaceutical Composition was administered to 20 healthy subjects for 21 days in a Phase 1 study in which 8% Test Pharmaceutical Composition was shown to be safe and well tolerated with low plasma exposure (highest observed plasma spiro-oxindole concentrations ⁇ 1 ng/mL).
• topically administered pharmaceutical compositions comprising the spiro-oxindole compound showed a generally favorable safety profile in nonclinical and clinical studies.
• the data for both oral and topically administered pharmaceutical compositions comprising the spiro-oxindole compound support the continued evaluation of topical pharmaceutical compositions comprising the spiro-oxindole compound in clinical studies conducted in patients with chronic pain.
• the dosage regimens selected for this study are the 4% Test Pharmaceutical Composition and the 8% Test Pharmaceutical Composition, both in ointment form and each administered twice daily.
• the selected dosage regimens are based on results from animal pharmacology studies, safety information from previous toxicology and clinical studies, and clinical efficacy previously observed with topical pharmaceutical compositions comprising the spiro-oxindole compound.
• the safety profile is anticipated to be similar to that observed previously in the postherpetic neuralgia and EM studies.
• signals of efficacy were observed in both the postherpetic neuralgia and EM studies in which 8% Test Pharmaceutical Composition was applied twice daily. Therefore, it is reasonable to include the 8% Test Pharmaceutical Composition dose as a high dose in this proof-of-concept study in postherpetic neuralgia.
• the study population will comprise approximately 330 patients (men and women) 18 years of age or older and with chronic postherpetic neuralgia. Approximately 330 patients (110 per treatment group) will be randomly assigned to 4% Test Pharmaceutical Composition, 4% Test Pharmaceutical Composition, or placebo to ensure that approximately 88 patients per group complete the treatment period, i.e., have the week 4 visit (visit 5, day 29).
• Patients must have chronic postherpetic neuralgia according to the definition of pain present for more than 6 months and less than 6 years after onset of herpes zoster skin rash affecting a single dermatome. Patients with more than 1 involved dermatome may also be included, provided the affected dermatomes are contiguous. The patient's average daily pain must be at least 4 on the 11-point NRS at screening and during the baseline pain assessment interval (days ⁇ 7 to ⁇ 1) immediately before study randomization. Patients with postherpetic neuralgia involving trigeminal dermatomes are excluded from the study.
• the primary objective of this study is to evaluate the efficacy of 4 weeks of topical administration of 4% Test Pharmaceutical Composition and 8% Test Pharmaceutical Composition of the invention compared with placebo for the relief of pain due to postherpetic neuralgia, as assessed by the change from baseline to week 4 in the weekly average of the daily average NRS scores.
• the daily average NRS score is the average of the 2 NRS scores (recorded in the morning and in the evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours.
• the exploratory objectives of the study are to evaluate topical 4% Test Pharmaceutical Composition and 8% Test Pharmaceutical Composition compared with placebo by examining the following:
• the screening period consists of a screening visit (informed consent and preliminary eligibility assessment are obtained); a washout phone contact during which eligibility based on laboratory test results will be reviewed and, as needed, patients will be given instructions to washout (discontinue) oral analgesic or topical pain therapy; a washout interval (if needed) of variable/flexible length during which appropriate patients will discontinue oral analgesic therapy, topical pain therapy, and/or non-pharmacologic therapies; and a baseline pain assessment interval, when each eligible patient will be given an electronic diary (eDiary) to record pain intensity from days ⁇ 10 to ⁇ 1.
• eDiary electronic diary
• baseline pain assessment will be defined as the last 7 days prior to randomization, i.e., calculated from the values recorded from days ⁇ 7 through ⁇ 1.
• rescue medications for postherpetic neuralgia pain will not be allowed.
• Rescue medication will also not be allowed during the last 7 days of treatment.
• patients will use eDiaries to record pain, using an 11-point NRS each morning (0700 ⁇ 2 hours) and evening (1900 ⁇ 2 hours), and any rescue pain medication usage.
• 3-mm skin punch biopsies will be taken from the area of postherpetic neuralgia pain and a contralateral homologous site at visit 3 (day 1, randomization).
• the NPSI and the DSIS will be administered, and the results will be recorded.
• the results of maximal intensity evoked allodynia and maximal intensity evoked hyperalgesia will be recorded.
• the NePIQoL will be evaluated at visit 3 (day 1, randomization) and visit 5 (day 29, week 4).
• the PGIC will be evaluated at visit 4 (day 15 ⁇ 1, week 2) and visit 5 (day 29, week 4). Efficacy measures are not collected at visit 6, except for ET visits.
• the patient will identify the location of his/her most severe allodynia, and this location will be used for assessments at all subsequent visits. If allodynia or hyperalgesia is not present at screening, it will not be tested at subsequent visits.
• the investigator will establish normal sensation by using a standardized 1-inch foam brush (light pressure just sufficient to bend the tip of the brush) to stroke an area of skin that is unaffected by pain.
• the region of allodynia will then be mapped by applying brush strokes moving from normal skin toward the painful region.
• a felt-tip pen will be used to mark the point where sensation changes from normal to painful. This process will be repeated until 8 to 10 points are marked in a radial fashion to define the area of allodynia.
• the marks will then be connected with a continuous line.
• the investigator will use the brush to perform 3 brush strokes within the mapped area of allodynia.
• the pain will be rated for intensity (using the highest pain rating reported) both at prebrush testing and during application of the brush and recorded; additionally, the difference between the 2 scores will be calculated and recorded.
• the patient will identify the location of his/her most severe hyperalgesia, and this location will be used for assessments at all subsequent visits.
• a Medipin will be applied in 3 successive applications to the area of skin identified at screening. The tip of the Medipin rests upon a flange, and the examiner should apply the pin so that the flange rests upon the skin without indenting it.
• acetaminophen (TYLENOL®, McNeil Consumer Healthcare Division of McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take 1 to 2 tablets per dose every 6 hours, as needed, and up to 6 tablets or 1950 mg per day (over a 24-hour period) for rescue relief of postherpetic neuralgia pain.
• Rescue medication will be provided at the screening visit. Rescue medication compliance will be checked at all visits until used rescue medication is collected after the baseline pain assessment interval or at randomization for patients not continuing in the study, at visit 5 (day 29, week 4) for patients who complete the treatment period, or at the ET visit for patients who prematurely discontinue study drug.
• Randomization will be stratified by test results of the pharmacogenomic sample collected at the screening visit (homozygous minor allele [positive, AA], heterozygous [positive, AG], and homozygous common allele [negative, GG]) for R1150W polymorphism in the SCN9A gene. The patient will be instructed on how to apply the study drug. Under study center staff supervision, the area affected by postherpetic neuralgia pain will be carefully defined by mapping the area of pain, and dosing will be prescribed to fully cover the affected area.
• Efficacy assessments of pain NRS, NPSI, NePIQoL, and DSIS scores will be conducted at visit 3 (day 1) to establish baseline measurements.
• the site staff will apply the first dose of blinded study drug and the patient will record the date/time in the eDiary.
• Subsequent study drug applications will be performed by the patient at home. (If the affected area is not within reach of application by the patient [such as the posterior thoracic region], the patient's designated caregiver will apply the ointment, but the patient will record the time of application in the eDiary.)
• the efficacy evaluation NePIQoL will also be performed, and the eDiary will be collected along with the tubes of study drug and bottles of rescue medication. Patients will be instructed to return to their primary care physician to resume therapy deemed appropriate for their postherpetic neuralgia.
• Patients who prematurely discontinue study drug will have an ET visit within 2 weeks after the last study drug administration. During the ET visit, the same activities will be conducted as those administered for follow-up at visit 6, the eDiary and any unused study drug/rescue medication will be collected, and compliance checks will be performed. Any treatment-emergent adverse event or serious adverse event will be monitored at suitable intervals until resolved, stabilized, or returned to baseline; until the patient is referred to the care of a health care professional; or until a determination of a cause unrelated to the study drug or study procedure is made during the study period.
• the study period is defined for each patient as that time period from signature of the Informed Consent Form (ICF) through the end of the follow-up period, day 57 ( ⁇ 3).
• ICF Informed Consent Form
• the ET visit will be the last study visit.
• the primary efficacy endpoint for this study is the change from baseline to week 4 in the weekly average of the daily average NRS scores.
• the daily average NRS score is the average of the 2 NRS scores (recorded in the morning and in the evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours.
• Test Pharmaceutical Composition The safety of 4% Test Pharmaceutical Composition and 8% Test Pharmaceutical Composition will be assessed throughout the study by evaluating adverse events, clinical safety laboratory test results, vital signs measurements, ECG and physical examination results, dermal irritation, and concomitant medication usage. Skin rashes or skin irritation in the area of ointment application will be evaluated using a dermal irritation scale (modified Draize scale) at day 1 (at 1 hour after application of study drug), week 2, week 4, and week 8 for follow-up.
• dermal irritation scale modified Draize scale
• Test Pharmaceutical Composition 4% Test Pharmaceutical Composition and 8% Test Pharmaceutical Composition will be assessed during the study using safety endpoints that also represent patients' experience of treatment, such as skin rashes and skin irritation.
• Two blood samples will be collected from each subject following 2 weeks of treatment with either 4% Test Pharmaceutical Composition or 8% Test Pharmaceutical Composition or matching placebo ointment, to quantitate the concentration of the spiro-oxindole in plasma.
• Patients will go to the study center after applying study drug at home so that the 2 pharmacokinetic samples can be taken.
• the first sample will be taken within approximately 1 to 4 hours of the morning dose of study drug and the second sample taken approximately 2 hours after collection of the first sample.
• the date and time of the morning dose and the date and exact time for each of the 2 pharmacokinetic samples will be recorded. Plasma samples will be analyzed for the spiro-oxindole compound.
• Pharmacodynamic endpoints assessed during the study are the following secondary efficacy endpoints: change from baseline in maximal intensity of patients' brush-evoked allodynia and maximal intensity of punctate-evoked hyperalgesia.
• Two blood samples (approximately 10 mL total) for pharmacogenomic analyses will be taken from all patients at the screening visit (visit 1) at approximately the same time as the clinical safety laboratory samples are collected. Patients who refuse to give these blood samples will be excluded from the study.
• One sample will be analyzed to identify the nucleotide (G or A) underlying the R1150W polymorphism in the SCN9A gene and may identify whether there are any other sequence variants in the SCN9A gene region. All samples will be retained for a maximum of 15 years after completion of the study and may be analyzed for other genetic variations potentially associated with pain signaling or drug response, including efficacy, metabolism, and safety parameters.
• a pharmacogenomic blood sample may be used to assess the polymorphisms of the CYP3A4 and CYP2C19 genes. Depending on the distribution of allelic variations for CYP3A4 and CYP2C19, these results may be incorporated as covariates in the current or future population pharmacokinetic analyses.
• Pharmacogenomic results for the R1150W polymorphism will be included as appropriate as part of the analyses of primary and secondary efficacy endpoints stratified by R1150W polymorphism status: homozygous minor allele (positive, AA) and heterozygous (positive, AG) versus homozygous common allele (negative, GG). Exploratory analyses may be reported separately from the main study results.
• Placebo ointment is a vehicle-only ointment with identical excipients, content (other than the active pharmaceutical ingredient), appearance, packaging, and labeling to the active treatments.
• the study drug is a double-blind 4% Test Pharmaceutical Composition, 8% Test Pharmaceutical Composition or placebo ointment for topical administration.
• 4% Test Pharmaceutical Composition, 8% Test Pharmaceutical Composition and matching placebo ointments are unscented, off-white to yellowish, opaque ointments with a smooth texture.
• the ointments contain the same excipients and differ only in the amount of active pharmaceutical ingredient (the matching placebo ointment contains only the excipients).
• the study ointments will be supplied to the study centers as 50-g fills in 60-mL plastic laminate tubes with tamper-evident seals. The tubes will be stored at ambient room temperature (15° C. to 25° C.).
• Study drug will be given to the patients. Study drug will be applied twice daily to the painful area in the morning (0700 ⁇ 2 hours) and again in the evening (1900 ⁇ 2 hours) from days 1 through 28. Study drug will be applied at approximately 3 ⁇ L/cm 2 per application. The actual amount (mg of ointment) of study drug per application will be measured (as length of ointment) using one or more dosing cards based upon the area of pain determined at randomization (visit 3, day 1).
• Patients will be provided with a laminated instruction sheet, including pictures, that will both describe and illustrate how the ointment is to be spread over the entire area of postherpetic neuralgia pain in a thin layer that fully covers the area.
• the ointment should be lightly massaged into the skin to cover the entire area of postherpetic neuralgia pain.
• the first application of study drug will occur at the study center on the day of the randomization visit (visit 3, day 1).
• the study coordinator or designated site staff member will apply blinded study drug and will define the amount of ointment to be used for all subsequent treatment applications for that patient.
• Dosing cards and instructions will be provided on how to measure the appropriate amount of ointment for each application.
• Caretakers will be provided instructions at the randomization visit on how to apply ointment to areas inaccessible to the study patient.
• the patients will apply blinded study drug twice daily (morning [0700 ⁇ 2 hours] and evening [1900 ⁇ 2 hours]) on the target area for 4 weeks from days 1 through 28.
• the morning dose might not be applied at 0700 ⁇ 2 hours because the first dose of study drug will be applied at the randomization visit (visit 3, day 1).
• the evening dose for day 1 should be applied at 1900 ⁇ 2 hours.
• Compliance will be assessed by weighing tubes at visit 3 (baseline), visit 4 (day 15 ⁇ 1, week 2), and visit 5 (day 29, week 4), or ET visit. A patient will be considered compliant during the interval between the previous 2 visits if the tube weighs between 70% and 120% of the expected weight.
• This study will consist of a screening period of up to 4 weeks, including a variable-length washout of oral analgesic therapy or topical pain therapy if needed, a 4-week double-blind treatment period, and a 4-week follow-up period. Patients are expected to participate in this study for about 12 weeks.
• a patient may withdraw participation in the study at any time for any reason (e.g., lack of efficacy, consent withdrawn, or adverse event).
• the investigator and/or Sponsor can withdraw a patient from the study at any time for any reason.
• the Sponsor may terminate the study for any reason and at any time.
• Day ⁇ 1 is the day before study day 1.
• Day 1 is the day of both randomization and the first dose (application) of study drug.
• the screening visit should occur no more than 28 days before randomization; day ⁇ 28 is the earliest possible day for the screening visit.
• c Variable/flexible date, depending on the need for washout and the drug(s) to be washed out.
• the baseline visit (day ⁇ 10) and the randomization visit (baseline +10; day 1) must be confirmed as weekdays.
• No time window (in days) is permitted for visit 5 (day 29, week 4).
• the washout phone contact (approximately 1 week after the screening visit or day ⁇ 21 at the earliest) will be the start of the washout interval (day of the phone contact through the day before the baseline visit) during which, if needed, the patient will discontinue medications used to treat PHN pain, including opioids (rescue medications [protocol-specified and provided acetaminophen only] permitted during the washout interval).
• the duration of the washout interval will vary from patient to patient depending on which (if any) medications need to be discontinued. For patients who do not need to washout medications, the other activities in this phone contact (review of eligibility based on laboratory test results and scheduling the baseline visit) will be performed.
• the baseline visit (day ⁇ 10) will be the start of the baseline period during which baseline information regarding pain will be collected while the patient refrains from all PHN rescue medications.
• h Performed prior to first dose of study drug. i Includes specific query regarding past use of topical therapy such as the 5% lidocaine patch or capsaicin. j includes heart rate, respiration rate, body temperature, and blood pressure. k Includes body weight (screening and follow-up/ET visits only) and height (screening visit only). l All ECGs will be taken in triplicate and read by a central reader for the study. The central reader will be blinded (will not know the randomization assignment of the patients). m Only for women of child-bearing potential. n For brush or punctate mechanical hyperalgesia.
• p Provide eDiary to eligible patients and instructions on using it to record daily pain (11-point NRS), date/time of study drug applications, and rescue medication usage.
• q Review eDiary and review eDiary data via website. Also, for patients not eligible to be randomly assigned to treatment, collect eDiary at the randomization visit (visit 3, day 1). r Review eDiary, review eDiary data via website, and collect eDiary.
• the eDiary will be used to record responses to 11-point NRS each morning (0700 ⁇ 2 hours) and each evening (1900 ⁇ 2 hours) before applying the study drug.
• the morning applications should take place after recording the morning (0700 ⁇ 2 hours) responses to the 11-point NRS, and the evening applications should take place after recording the evening (1900 ⁇ 2 hours) responses to the 11-point NRS.
• the morning dose might not be applied at 0700 ⁇ 2 hours because this first dose of study drug will be applied at the randomization visit.
• the evening dose for day 1 should be applied at 1900 ⁇ 2 hours.
• z First dose will be applied by study site staff at randomization visit (visit 3, day 1). aa At visit and home on day 1; at home from day 2 onward. bb At home through the evening of day 28. cc Performed after first dose of study drug.
• DSIS Daily Sleep Interference Scale
• ECG electrocardiogram
• eDiary electronic diary
• ET early termination
• NePIQoL Neuropathic Pain Impact on Quality of Life questionnaire
• NPSI Neuropathic Pain Symptom Inventory
• NRS Numeric Rating Scale
• PGIC Patient Global Impression of Change
• PHN postherpetic neuralgia
• PK pharmacokinetics
• V5 visit 5. Screening Visit (Visit 1, Day ⁇ 28)
• the screening visit will be no more than 28 days before randomization/first dose of study drug.
• a signed and dated informed consent form will be obtained before screening procedures commence.
• a patient who is screened and does not meet study entry criteria will not be considered for screening again.
• a patient taking prohibited concomitant medications may be allowed to continue with study procedures if the investigator or designee believes that the patient can discontinue the prohibited medications during the 4-week screening period and remain off the prohibited medications through the week 4 (visit 5, day 29) or the ET visit.
• the screening visit (visit 1) will take place ⁇ 28 days before the first dose (application) of study drug scheduled to be given in the clinic at the randomization visit (visit 3) on day 1.
• the following procedures to determine patient eligibility for the study will be performed at the screening visit:
• the patient will identify the location of his/her most severe hyperalgesia, and this location will be used for assessments at all subsequent visits.
• Two blood samples will be collected for pharmacogenomic analysis.
• a patient's refusal to provide the pharmacogenomic blood samples will disqualify the patient from participation in the study.
• washout phone contact will be no more than 21 days before randomization/first dose of study drug, since it takes place 1 week after visit 1.
• study eligibility based on laboratory test results will be reviewed, the initial adverse event inquiry will be performed, rescue medication use (if any) will be reviewed and recorded as concomitant medication, prior/concomitant medications will be reviewed, and as needed, patients will be given instructions to washout (discontinue) oral analgesic therapy, topical pain therapy, or non-pharmacologic therapy.
• this phone contact will be used for other activities needed at this point in the study (review of eligibility based on laboratory test results, initial inquiry for adverse events, review and recording of any rescue medication use, review of prior/concomitant medications as needed, and scheduling the baseline visit).
• Washout Period (Variable Duration Period Between the Washout Phone Contact and the Baseline Visit)
• washout period of variable/flexible length will take place, during which the patient will discontinue oral analgesic therapy, topical pain therapy, and/or non-pharmacologic therapies before initiation of the baseline period.
• the duration of the washout interval will vary from patient to patient, depending on which (if any) medications need to be discontinued.
• acetaminophen (TYLENOL, McNeil Consumer Healthcare Division of McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take 1 to 2 tablets per dose every 6 hours, as needed, and up to 6 tablets or 1950 mg per 24-hour day.
• Patients who continue to meet the inclusion/exclusion criteria will be assigned a permanent unique randomization number and a treatment number using an IRT. These 2 newly assigned numbers will be entered into the CRF, and study drug will be dispensed.
• the randomization visit occurs on the same day as the start of study drug treatment. This visit must be confirmed as a weekday upon scheduling.
• Randomization will be stratified by test results of the pharmacogenomic sample collected at the screening visit (homozygous minor allele [positive, AA], heterozygous [positive, AG], and homozygous common allele [negative, GG]) for R1150W polymorphism in the SCN9A gene.
• the site of the skin biopsy will be covered with a small circular bandage that will be changed daily and may be removed when healed, typically within a few days.
• the area affected by postherpetic neuralgia pain will be carefully defined by the investigator and the patient by mapping the area of pain. Dosing of the test ointments will be prescribed to fully cover the affected area. The ointment should be applied to the margin of the biopsy site bandage but not covering the bandage. The following procedures/assessments will be performed at visit 3 immediately prior to or at the time of the first study drug dose:
• topical study drug (4% Test Pharmaceutical Composition, 8% Test Pharmaceutical Composition or placebo) according to the instructions provided by the study center.
• Study drug will be applied twice daily (in the morning [0700 ⁇ 2 hours] and again in the evening [1900 ⁇ 2 hours]).
• the first dose of study drug will be applied at the clinic on day 1 during the randomization visit. Regardless of the clock time of the first dose application at the randomization visit, the evening dose for day 1 should be applied at 1900 ⁇ 2 hours.
• the last dose of study drug will be applied at home on the evening of day 28. No study drug will be applied on day 29, the day of visit 5 (week 4).
• the follow-up visit activities plus eDiary and unused study drug/rescue medication collection (and compliance checks) will be conducted at the ET visit, for ET visits occurring prior to visit 5 (day 29, week 4). An ET visit may also occur after visit 5 but before the day that visit 6 would normally be scheduled, on day 57 ⁇ 3. If adverse events or other safety findings are present at the ET visit, the clinical course of each adverse event will be monitored at suitable intervals until resolved or stabilized or returned to baseline, until the patient is referred to the care of a health care professional, or until a determination of a cause unrelated to the study drug or study procedure is made. Otherwise, the ET visit will be the last study visit for these patients.
• acetaminophen (TYLENOL, McNeil Consumer Healthcare Division of McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take 1 to 2 tablets per dose every 6 hours, as needed, and up to 6 tablets or 1950 mg per day (over a 24-hour period) for rescue relief of postherpetic neuralgia pain.
• Rescue medication will be provided at the screening visit. Rescue medication compliance will be checked at all visits until used rescue medication is collected after the baseline pain assessment interval for patients not continuing in the study, at visit 5 (day 29, week 4) for patients who complete the treatment period, or at the ET visit for patients who prematurely discontinue study drug.
• the total amount of blood drawn during the study from each patient will be approximately 50 mL.
• An adverse event can include any of the following:
• a serious adverse event is an adverse event occurring at any dose that results in any of the following outcomes or actions:
• Any patient becoming pregnant during the study will be withdrawn from study drug treatment. All patients (or female partners of male patients) who become pregnant will be monitored to the completion or termination of the pregnancy. If the pregnancy continues to term, the outcome (health of the infant up to 8 weeks of age), details of birth, and presence or absence of any birth defect, congenital abnormalities, or maternal and newborn complications will be reported to the Sponsor. Any complication of pregnancy will be reported as an adverse event or serious adverse event, as appropriate.
• Urinalysis will include testing for the following:
• Urine pregnancy tests will be performed at the study site (with test kits provided by a central laboratory) for all women of child-bearing potential at screening (visit 1), randomization (visit 3, day 1), visit 4 (day 15 ⁇ 1, week 2), visit 5 (day 29, week 4), and at the follow-up/ET visit (visit 6, day 57 ⁇ 3). Any patient who becomes pregnant during the study will be withdrawn.
• a urine drug screen will be performed at the time points indicated in Table 8.
• the urine drug screen includes a means to detect the presence of drugs prohibited according to the protocol, including cannabinoids, alcohol, cocaine, amphetamines, barbiturates, benzodiazepine, and opiates. If a parameter noted above cannot be tested using urine, an alternative matrix (e.g., serum) may be considered acceptable.
• an alternative matrix e.g., serum
• the Sponsor's medical expert must be made aware in advance of, and provide approval for, drug screen parameters to which this will apply. A positive result for any of the above drugs or their metabolites, without medical explanation, will preclude the patient from enrollment or continued participation in the study.
• Vital signs will be measured at the time points indicated in Table 8. Vital signs include the following:
• a 12-lead ECG will be conducted as triplicate tracings taken at least 1 minute apart at the time points indicated in Table 8. To determine eligibility based upon numerical exclusion criteria of cardiac intervals, the investigator will use the mean values of 3 ECGs. A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. Any ECG finding that is judged by the investigator as a clinically significant change (worsening) compared with a baseline value will be considered an adverse event, recorded on the source documentation and transcribed onto the CRF.
• Pharmacodynamic endpoints assessed during the study are the secondary efficacy endpoints change from baseline in maximal intensity of patients' brush-evoked allodynia and change from baseline in maximal intensity of patients' punctate-evoked hyperalgesia.
• the primary objectives of this study were to determine the effects of multiple-dose topical treatment with the 8% Test Pharmaceutical Composition on the single-dose pharmacokinetics of oral midazolam and to determine the effects of multiple-dose topical treatment with 8% Test Pharmaceutical Composition on the single-dose pharmacokinetics of oral omeprazole.
• the secondary objectives of the study were to characterize the pharmacokinetics of the spiro-oxindole compound; to characterize the pharmacokinetics of midazolam and omeprazole major metabolites, 1-OH-midazolam and 5-OH-omeprazole; to evaluate the safety and tolerability of the 8% Test Pharmaceutical Composition administered twice daily (BID) for 7.5 days.
• the primary pharmacokinetic endpoints were the geometric mean ratios (90% confidence intervals [CIs]) for C max , AUC 0-t , and AUC 0-inf for midazolam and omeprazole on day 9 versus day 1.
• the secondary pharmacokinetic parameters for midazolam and omeprazole were time to maximum observed plasma drug concentration (t max ), apparent oral clearance (CL/F), apparent terminal elimination rate constant ( ⁇ z ), apparent terminal half-life (t 1/2 ), and percentage extrapolated AUC (AUC ext ).
• cytochrome P450 family 2, subfamily C, polypeptide 19 (CYP2C19) metabolic status of subjects were collected for the assessment of cytochrome P450 family 2, subfamily C, polypeptide 19 (CYP2C19) metabolic status of subjects.
• the within-subject coefficient of variation (% CV) for midazolam pharmacokinetic parameters (C max , AUC) was estimated to be 21%. Assuming a within-subject CV of 21% and an expected true ratio of 1.05 for day 9 versus day 1, a total of 28 subjects completing the study would provide at least 90% power to detect bioequivalence in a single pharmacokinetic parameter of midazolam before and after multiple administration of the spiro-oxindole compound at the 0.05 significance level for a 1-sided test. Assuming a 10% to 20% discontinuation rate, 4 additional subjects were included so that a total of 32 subjects were enrolled in this study.
• This sample size also provided approximately 86% power to detect bioequivalence in a single omeprazole pharmacokinetic parameter (AUC) before and after multiple administration of the spiro-oxindole compound at the 0.05 significance level, assuming a within-subject CV of 26% and an expected true ratio of 1.0. SAS® proc power was used for sample size calculation.
• Descriptive statistics (n, mean, geometric mean, standard deviation [SD], % CV, median, minimum, and maximum) were used to summarize plasma midazolam, omeprazole and their metabolites, and the spiro-oxindole compound concentration for all subjects overall at each scheduled time point. Descriptive statistics (as noted above) were also used to summarize plasma omeprazole, 5-OH-omeprazole, and the spiro-oxindole compound concentration for all subjects overall by CYP2C19 genotype at each scheduled time point. Pharmacokinetic parameters were derived by noncompartmental analysis.
• Descriptive statistics were used to summarize the calculated pharmacokinetic parameters for midazolam, omeprazole and their metabolites, and the spiro-oxindole compound by treatment for all subjects.
• Descriptive statistics were also used to summarize the calculated pharmacokinetic parameters for omeprazole, 5-OH-omeprazole, and the spiro-oxindole compound by treatment and CYP2C19 genotype. Plots of geometric mean and individual plasma concentrations and of select pharmacokinetic parameters for midazolam, omeprazole and their metabolites and the spiro-oxindole compound at select sampling times were provided. Additionally, plots of individual select pharmacokinetic parameters by CYP2C19 phenotype for omeprazole at select time points were provided.
• a total of 94 healthy subjects were screened for enrollment into this study.
• 32 subjects at 1 center in the USA met entry criteria and were considered to be eligible for enrollment into the study.
• 4 subjects were excluded on the basis of inclusion criteria
• 47 subjects were excluded on the basis of exclusion criteria
• 3 subjects withdrew consent 1 subject was lost to follow up before the baseline visit
• 7 subjects were excluded based on “Other” reasons.
• 32 subjects enrolled all received at least 1 administration of study drug and were evaluated for safety and pharmacokinetics. The planned number of 32 subjects was met.
• Subjects had a mean age of 35.1 years (range: 19 to 50 years), a mean weight of 76.81 kg (range: 54.1 to 98.5 kg), a mean height of 173.92 cm (range: 155.0 to 188.0 cm), a mean BMI of 25.42 kg/m2 (range: 19.2 to 32.0 kg/m2), and a mean BSA of 1.92 m2 (range: 1.6 to 2.3 m2).
• CYP2C19 phenotype subjects were evenly distributed for ultra-rapid, extensive, and intermediate metabolizers (10 [31%] subjects each). Only 2 (6%) subjects were classified as poor metabolizers.
• midazolam concentrations were similar with or without coadministration of the spiro-oxindole compound. On both days 1 and 9, midazolam appeared to be rapidly absorbed as it was quantifiable in all subjects by 0.25 hours postdose. Upon reaching a peak, midazolam concentrations declined steadily in a multiphasic manner. Most subjects had measurable concentrations through to at least 16 hours postdose.
• omeprazole concentrations were similar with or without coadministration of the spiro-oxindole compound. On both days 1 and 9, 0.75 to 1.5 hours elapsed before omeprazole concentrations were quantifiable in a majority of subjects. Upon reaching a peak, omeprazole concentrations declined steadily in a multiphasic manner until no longer quantifiable, which was between 9 to 12 hours in most subjects. In a few subjects, omeprazole remained quantifiable until 16 to 24 hours.
• omeprazole After oral administration of a single dose of 3 mg midazolam and 20 mg omeprazole, omeprazole was absorbed reaching tmax at median times of 2.0 and 2.5 hours on days 1 and 9, respectively.
• Systemic exposure parameters (C max and AUC) for omeprazole were similar on both days 1 and 9.
• Geometric mean C max was 227.39 ng/mL on day 1 and 227.04 ng/mL on day 9.
• geometric mean AUC 0-t and AUC 0-inf were 545.29 and 634.65 hr*ng/mL, respectively, while on day 9, they were 556.16 and 633.97 hr*ng/mL, respectively.
• AUC 0-t accounted for >99% of AUC 0-inf .
• omeprazole was metabolized to its 5-OH metabolite.
• t max of 5-OH-omeprazole was reached at a median time of 2.00 hours, while on day 9, median t max was 2.5 hours.
• Systemic exposure parameters (C max and AUC) for 5-OH-omeprazole were similar on both days 1 and 9.
• Geometric mean for C max was 148.71 ng/mL on day 1 and 142.30 ng/mL on day 9.
• Geometric AUC 0-t and AUC 0-inf were 436.73 and 447.15 hr*ng/mL, respectively, on day 1, and 430.54 hr*ng/mL and 439.66 hr*ng/mL on day 9.
• concentrations were highly variable over the first 24 hours, often reaching multiple peaks. All 31 subjects had quantifiable concentrations at 24 hours postdose (mean 11651.61 pg/mL) and at the follow-up visit (360 ⁇ 24 hours; mean 326.29 pg/mL). Over the period of 24 hours from the final application of the 8% Test Pharmaceutical Composition, concentrations varied from a geometric mean C trough predose value) of 12760.52 pg/mL to a C max of 15072.40 pg/mL.
• geometric mean AUC 0-12 was 132906.66 hr*pg/mL, with an average concentration of 11075.55 pg/mL over this 12-hour period, which coincided with the oral administration of midazolam and omeprazole.
• Midazolam the model substrate for CYP3A4, was coadministered with multiple doses of the spiro-oxindole compound. There was no evidence of a clinically meaningful effect of a topical formulation of the spiro-oxindole compound under exaggerated dosing conditions on the pharmacokinetics of oral midazolam, a sensitive probe CYP3A4 substrate, or its metabolite 1-OH-midazolam.
• Omeprazole the model substrate for CYP2C19, was coadministered with multiple doses of the spiro-oxindole compound. There was no evidence of a significant effect of topical formulation of the spiro-oxindole compound under exaggerated dosing conditions on the pharmacokinetics of oral omeprazole, a sensitive probe CYP2C19 substrate, or its metabolite 5-OH-omeprazole.

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